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Reducing Flares in Atopic Dermatitis by Managing Subclinical Inflammation

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 22nd World Congress of Dermatology

Seoul, South Korea / May 24-29, 2011

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Pathophysiology

As explained here at the WCD by Dr. Michael Cork, Head, Academic Unit of Dermatology Research, The University of Sheffield, UK, an intact stratum corneum serves as a barrier against penetration of irritants and allergens into the skin, and protects against transepidermal water loss (TEWL).

In his review of epidermal barrier dysfunction (J Invest Dermatol 2009;129:1892-908), a disturbance in epidermal barrier function is one of the primary events in the development of atopic dermatitis (AD) and changes in or variants of genes that regulate barrier function predispose patients to AD. Researchers have now identified changes in at least 3 groups of genes that encode for structural proteins, epidermal proteases and protease inhibitors. These mutations increase the risk of developing AD; loss-of-function mutations found within the filaggrin genes are the most significant. As Dr. Cork pointed out, enhanced protease activity and decreased synthesis of the lipid lamella both exacerbate epidermal barrier breakdown.

Environmental factors including the use of soap and detergents also increase the pH in the stratum corneum, further exacerbating epidermal barrier breakdown. When the increase in skin pH is sustained, the activity of degradatory proteases increases while simultaneously decreasing the activity of lipid synthesis enzymes. A defective epidermal barrier allows allergens into the skin where they interact with local immune effector cells through antigen-presenting cells, triggering the IgE-mediated allergic response in most patients with AD.

“The strong association between both genetic barrier defects and environmental insults to the barrier [in patients] with AD suggests that epidermal barrier dysfunction is a primary event in the development of this disease,” Dr. Cork wrote. “Our understanding of gene-environment interactions should lead to a better use of some topical products, avoidance of others, and increased use and development of products that can repair the skin barrier.”

Avoiding Treatment that Disrupt the Epidermal Barrier

Dr. Cork presented evidence at the WCD that topical corticosteroids (TCS) have a detrimental effect on skin barrier function and it may be best to avoid as long-term therapy.

He and colleagues did a comparative study of the effect of applying either the topical calcineurin inhibitor (TCI) tacrolimus ointment (0.1%) b.i.d. or betamethasone valerate (0.1%) b.i.d. to the forearm for 4 weeks. They found that the TCI ointment improved barrier function as measured by the degree to which treatment affected TEWL, whereas the TCS decreased it.

Researchers at the University of Sheffield have also shown that TCS induce protease activity in the skin, whereas TCIs do not, suggesting that these agents are not likely to disrupt the epidermal barrier.

Treating Subclinical Inflammation: A Proactive Approach

In his discussion on clinical and subclinical inflammation in AD (Eur Derm 2010;5:28-31), Dr. Thomas Bieber, Chair and Director, Department of Dermatology, Friedrich-Wilhelms University, Bonn, Germany, argued that the current “reactive” approach to treat AD flare episodes is not physiologically suited to the chronic inflammatory nature of the disease. “It is now understood that clinically unaffected skin of patients with AD is not ‘normal’ and that after the clinical signs of flare have resolved, subclinical inflammation persists,” he stated in his review. Failure to treat subclinical inflammation may, in fact, contribute to recurrent flares, he added.

As an alternative, Dr. Bieber suggested that a “proactive” approach during which patients receive high-intensity anti-inflammatory therapy to induce disease remission, followed by maintenance therapy with low-dose anti-inflammatory drugs to sustain the remission, may improve outcomes for patients with AD. In evaluating the data for proactive approaches, Dr. Bieber reviewed several studies in his paper, one of which (BMJ 2003;326:1367) included 376 patients with moderate to severe AD who initially received high-intensity treatment with fluticasone propionate (FP) 0.05% cream or FP 0.005% ointment, q.d. or b.i.d. for 4 weeks. Some 295 patients whose disease was controlled continued into the maintenance phase where they were randomized to a proactive twice-weekly regimen involving the FP cream, the FP ointment or placebo. All patients used regular emollient therapy.

Median time to relapse during the maintenance phase was >16 weeks in those receiving proactive FP regimens vs. 6 weeks for the placebo arm. There was also a 5.8-fold lower risk of relapse in the proactive twice-weekly FP cream group vs. placebo and a 1.9-fold lower risk in the FP ointment group vs. placebo. This and related studies indicate that a proactive FP-based regimen can be efficacious in AD patients in disease remission.

Nevertheless, as Dr. Bieber pointed out, concerns about the long-term safety of the potent TCS include skin atrophy and stria formation, as well as systemic side effects, most notably growth retardation, a particular concern for parents of children with AD. Alternatives including TCI-based proactive therapy may be safer in the long-term, as Dr. Bieber suggested.

Long-term Maintenance: CONTROL Findings

As discussed by Dr. Diamant Thaçi, Director, Clinical Research Division, Department of Dermatology, Johann Wolfgang Goethe University, Frankfurt am Main, Germany, the currently recommended “step-wise” paradigm for the treatment AD is already shifting towards long-term maintenance therapy as better control of AD is more likely to prevent flares or at least prolong the interval between flares. One such regimen involves therapy with the TCI tacrolimus.

In the CONTROL studies published in 2008 (Allergy 2008;63:742-50, Br J Dermatol 2008;159:1348-56), all patients enrolled received tacrolimus ointment b.i.d. for up to 6 weeks until the Investigator’s Global Assessment (IGA) score was =2. Patients were then randomized to continue on the TCI ointment twice a week at a concentration of 0.03% for pediatric patients and 0.1% for adult, or to a flare treatment-only protocol.

At week 12, mean eczema area and severity index (EASI) scores dropped by 46.7% in adults receiving the twice-weekly regimen vs. no change in adults receiving the flare treatment-only regimen. In children, mean EASI scores dropped by 51% in the twice-weekly regimen group vs. a 6.7% reduction in those on the flare treatment-only regimen. In a more recent analysis of the CONTROL studies (J Dermatol Treatment 2010;21:34-44), investigators showed there were significantly fewer major flares among adults and children on the twice-weekly regimen than those on the flare treatment-only regimen (P<0.001) and significantly more patients on the twice-weekly regimen had no flares of any severity compared with control groups (P<0.001).

“Approximately 3 times more patients on twice-weekly treatment remained flare-free during 12 months vs. those on flare treatment only,” Dr. Thaçi observed, “and the median time to first major flare in the pediatric study was 217 days for the twice-weekly group vs. 36 days in the flare treatment-only group.” Time to first major flare in the adult study was also significantly longer at 142 days in the twice-weekly group vs. 15 days for the flare treatment-only group (Table 1).

Table 1.


The incidence of adverse events (AEs) and serious AEs was low and similar between active and flare only-treatment groups in both adult and pediatric studies.

A cost-effective analysis done by Thaçi et al. (J Eur Acad Dermatol Venereol 2010;24(9):1040-6) found that the cost of treating children with severe AD over 12 months was also lower with twice-weekly tacrolimus ointment than with the flare-only treatment. “With tacrolimus ointment, we have better disease control in the long term, fewer major flares, fewer clinical signs and symptoms of disease. Treatment is not adding to the cost in patients with more severe disease because in these patients, we also showed the twice-weekly regimen had a cost-saving effect as well,” Dr. Thaçi reaffirmed.

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